PROJECT SUMMARY Re-establishment of blood flow (reperfusion) through coronary arteries has reduced immediate death from acute myocardial infarctions (MI). However, the long-term complications in the chronic phase of MI, particularly chronic heart failure (CHF) culminating in major adverse cardiovascular events (MACE: hospitalization or death), have become epidemic. Currently, ~2 million MI patients in the US are living with CHF and their 5-year survival rate is < 50%. An important and long-established predictor of chronic heart failure is the acute MI size; but reducing acute MI size is limited by time to reperfusion. Over the past two decades, advances in cardiac MRI (CMR) have established that persistent microvascular obstruction (PMO) is another independent predictor of CHF. PMO is an acute feature of MI where microvascular blood flow to the MI territory is lost despite reperfusion. PMOs are estimated to be present in >60% of all acute MIs. Notably, results from an international consortium recently reported that the presence of PMO carries a 4-fold greater risk for MACE than acute MI size in the chronic period. Accordingly, therapeutic targeting of PMOs holds great promise for patients otherwise at risk of developing CHF. Yet, currently available post MI medications are not specific to patients with PMO; and they have not shown any incremental benefit to the patients with PMO over other MI types. Furthermore, although a significant effort has been spent on preventing PMO from occurring, it has not yet been possible to consistently achieve this. These observations have led to recent emphatic calls for improved understandings of how PMOs drive adverse remodeling in the chronic phase of MI so that effective therapeutics may be developed. Using animal models of chronic MI, in this proposal we aim to demonstrate that (a) PMOs resolve into iron crystals, which play a central role in driving the adverse remodeling; and (b) chelation of iron from the heart with deferiprone can significantly reduce adverse remodeling. Aim 1 will develop a CMR approach for accurate quantification of iron within MI zones; Aim 2 will demonstrate the mechanism driving the adverse remodeling; and Aim 3 will show that reducing iron within MI reduces adverse remodeling. To address these Aims, this proposal brings together a group of experts in cardiac imaging (MRI and PET), macrophage biology, post infarction remodeling, iron-chelation therapy and chemistry. Successful completion of this proposal will significantly impact clinical care of MI patients as the proposed iron chelation therapy will be rapidly translatable owing to its established clinical profile for safety and efficacy in treating other cardiac iron disorders.